The term “enantiomeric mixture” is known in the art and is understood to mean a mixture of two enantiomers.
The term “resolving enantiomers” is understood in the art to mean the increase of the relative amount of a particular enantiomer in an enantiomeric mixture. Such a resolving method can be used to obtain an enantiomerically pure compound from an enantiomeric mixture. The term “resolving agent” used herein is understood to mean an agent that can be used for resolving enantiomers.
Resolving methods, known in the art are based on preferential crystallisation of diastereomeric salts, formed by a reaction of the resolving agent with the enantiomeric compounds in the mixture. Diastereomeric salts are known to have different physical properties, such as crystallisation characteristics; it is known in the art to separate diastereomeric salts from one another based on the said different characteristics, by choosing the proper conditions therefor. Ideally, only the salt of one enantiomeric form of the enantiomeric compound of the mixture precipitates under the chosen conditions, whereas the salts of the other enantiomer remain in solution. Said precipitate can be further purified, resulting in an enantiomerically enriched, or enantiomerically pure compound. Instead of, or in addition to the precipitated fraction, the liquid fraction, the so-called “mother liquor” can be used for the purification of the non-precipitated salt, comprising the antipodic enantiomer of the mixture in enantiomerically enriched form. Herein, an enantiomer is deemed to be “enantiomerically enriched” when the said enantiomer is present in a higher molar amount than the other (antipodic) enantiomer.
Resolution of racemic compounds through formation and separation of diastereomeric salts is an important technology for the preparation of enantiopure products on an industrial scale. The finding of a suitable resolving agent is however, often, trial and error.
In the art, carboxylic acids are known as resolving agents for resolving a mixture of basic enantiomers; however, such compounds have a relatively weak acidity, resulting in limiting salt formation, which is particularly problematic for resolving weak basic compounds.
Further, 10-camphorsulfonic acid is known as resolving agent for basic enantiomeric mixtures, see Stereochem. Org. Compounds, E. L. Eliel, S. H. Wilen, Wiley Interscience, N.Y., U.S.A., 1994, pp. 322-337. However, the diversity in resolving agents, in particular in resolving weak basic enantiomers, in limited.